An abnormality of homocysteine thiolactone metabolism occurs in cultured malignant cells, as reported in Cancer Research 36:3198-3202, 1976. As a result of this abnormality homocysteine thiolactone reacts with protein amino groups, forming homocysteinyl peptide bonds and a free sulfhydryl group, a process known as thiolation. It was suggested that normal cells contain an N-substituted derivative of homocysteine thiolactone which prevents thiolation of proteins by homocysteine thiolactone, thereby preventing the malignant growth state characteristic of cancer cells. Certain N-substituted derivatives of homocysteine thiolactone, composed of normal biochemical constituents, pyridoxal and arachidonic acid, modify the growth of malignant neoplasms in mice, as reported in Chemotherapy 23:44-49, 1977. Several other N-substituted derivatives of homocysteine thiolactone, as taught in U.S. Pat. No. 4,383,994, consisting of N-maleyl homocysteine thiolactone amide, N-maleamide homocysteine thiolactone amide, oxalyl homocysteine thiolactone perchlorate, and rhodium trichloride oxalyl homocysteine thiolactone, decrease the growth of malignant neoplasms in animals. Encapsulation of N-maleamide homocysteine thiolactone amide within liposomes enhances its antineoplastic activity, as reported in Proceedings of the Society for Experimental Biology and Medicine, 180:57-61, 1985. Administration of rhodium trichloride oxalyl homocysteine thiolactone in a solution of mixed lipids enhances its antineoplastic activity (unpublished manuscript, 1985).
Retinoids, natural and synthetic compounds related to vitamin A (retinol), have been known for many years to modify the differentiation and growth characteristics of malignant neoplasms. In addition, retinoids are active in preventing the development of malignant neoplasms induced in animals by a variety of carcinogens. For a discussion of these biological characteristics of retinoids, see R. C. Moon and L. M. Itri, "Retinoids and Cancer" in The Retinoids, Volume 2, pp 327-372, Academic Press, 1984. Retinoic acid, the acid derivative of retinol, for example, is active in preventing the development of urinary bladder cancer in rats induced by carcinogens. A major disadvantage of the use of retinoids, including retinoic acid, for chemoprevention or chemotherapy of cancer is that these compounds exhibit marked cumulative toxicity, manifested by the hypervitaminosis A syndrome, as reviewed by W. Bollag, Lancet 1:860-863, 1983. The toxicity of retinoids has limited their usefulness in clinical trials of chemotherapeutic activity.
Homocysteine thiolactone is a product of methionine metabolism in liver, as reported in Biochimica et Biophysica Acta 343:687-691, 1974. A part of the homocysteine thiolactone produced by metabolism of methionine is bound to the lipids of liver cells. Homocysteine thiolactone hydrochloride produces atherosclerotic lesions in the arteries of experimental animals when injected parenterally, as reported in American Journal of Pathology 61:1-11, 1970. Homocysteine thiolactone perchlorate causes atherosclerotic lesions when fed in an experimental diet to animals, as reported in Atherosclerosis 22:215-227, 1975. Homocysteine thiolactone perchlorate, as taught in U.S. Pat. No. 4,255,443, affects the growth of malignant tumors. Homocysteine thiolactone free base is a reactive substance which is soluble in non-polar solvents and spontaneously dimerizes to the corresponding diketopiperazine derivative, as reported in Journal of Biological Chemistry 126:217-231, 1938.
Cyclophosphamide is an example of a commonly employed antineoplastic compound which has the disadvantage of cumulative toxicity after prolonged administration in cancer chemotherapy. The subject compound of this invention, N-homocysteine thiolactonyl retinamide, overcomes the disadvantage of toxicity of chemotherapeutic compounds and retinoids, because it is composed of retinoic acid and homocysteine thiolactone in a chemical form which prevents toxicity to normal cells and tissues. Because large doses of N-homocysteine thiolactonyl retinamide can be given without toxicity, the compound is useful for chemoprevention and chemotherapy of malignant neoplasms in animals.